Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction†

We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1

Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas

NRP1 (neuropilin-1) is a co-receptor for members of the VEGF (vascular endothelial growth factor) family in endothelial cells, but is increasingly implicated in signalling induced by other growth factors. NRP1 is expressed in VSMCs (vascular smooth muscle cells), but its function and the mechanisms involved are poorly understood. The present study aimed to determine, the role of NRP1 in the migratory response of HCASMCs (human coronary artery smooth muscle cells) to PDGF (platelet-derived growth factor), and to identify the signalling mechanisms involved. NRP1 is highly expressed in HAoSMCs (human aortic smooth muscle cells) and HCASMCs, and modified in VSMCs by CS (chondroitin sulfate)-rich O-linked glycosylation at Ser(612). HCASMC migration induced by PDGF-BB and PDGF-AA was inhibited by NRP1 siRNA (small interfering RNA), and by adenoviral overexpression of an NRP1 mutant lacking the intracellular domain (Ad.NRP1 Delta C). NRP1 co-immunoprecipitated with PDGFR alpha (PDGF receptor alpha), and immunofluorescent staining indicated that NRP1 and PDGFR alpha co-localized in VSMCs. NRP1 siRNA also inhibited PDGF-induced PDGFR alpha activation. NRP1-specific siRNA, Ad.NRP1 Delta C and removal of CS glycans using chondroitinase all inhibited PDGF-BB and -AA stimulation of tyrosine phosphorylation of the adapter protein, p130(Cas) (Cas is Crk-associated substrate), with little effect on other major signalling pathways, and p130(Cas) knockdown inhibited HCASMC migration. Chemotaxis and p130(Cas) phosphorylation induced by PDGF were inhibited by chondroitinase, and, additionally, adenoviral expression of a non-glycosylatable NRP1S612A mutant inhibited chemotaxis, but not p130(Cas) phosphorylation. These results indicate a role for NRP1 and NRP1 glycosylation in mediating PDGF-induced VSMC migration, possibly by acting as a co-receptor for PDGFR alpha and via selective mobilization of a novel p130(Cas) tyrosine phosphorylation pathway

VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation

In endothelial cells, neuropilin-1 (NRP1) binds vascular endothelial growth factor (VEGF)-A and is thought to act as a coreceptor for kinase insert domain-containing receptor (KDR) by associating with KDR and enhancing VEGF signaling. Here we report mutations in the NRP1 b1 domain (Y297A and D320A), which result in complete loss of VEGF binding. Overexpression of Y297A and D320A NRP1 in human umbilical vein endothelial cells reduced high-affinity VEGF binding and migration toward a VEGF gradient, and markedly inhibited VEGF-induced angiogenesis in a coculture cell model. The Y297A NRP1 mutant also disrupted complexation between NRP1 and KDR and decreased VEGF-dependent phosphorylation of focal adhesion kinase at Tyr407, but had little effect on other signaling pathways. Y297A NRP1, however, heterodimerized with wild-type NRP1 and NRP2 indicating that nonbinding NRP1 mutants can act in a dominant-negative manner through formation of NRP1 dimers with reduced binding affinity for VEGF. These findings indicate that VEGF binding to NRP1 has specific effects on endothelial cell signaling and is important for endothelial cell migration and angiogenesis mediated via complex formation between NRP1 and KDR and increased signaling to focal adhesions. Identification of key residues essential for VEGF binding and biological functions provides the basis for a rational design of antagonists of VEGF binding to NRP1

Method and Notation Application for Case Model Creation in the Social Sector

Adaptive Case Management (ACM) is an approach for the management of knowledge-intensive processes. “Case Management Model and Notation” (CMMN) is an industry standard that can be used as a notation for process models in the context of ACM. However, CMMN only specifies a notation. Methods for process elicitation and management have not been well addressed by scientific investigations. This work assesses the method support and the feasibility of ACM on the example of a social care company. This company, on the one hand, represents a typical environment for ACM application and, on the other hand, contains some characteristics that are common for the social care industry. Thus, future development directions, a combined process and case approach for the social care company and an evaluation of existing and proposed methodology are provided in a qualitative way

Transformative Wirtschaftswissenschaft im Kontext nachhaltiger Entwicklung : für einen neuen Vertrag zwischen Wirtschaftswissenschaft und Gesellschaft

In einem gemeinsamen Artikel regen die Autorinnen und Autoren die Diskussion eines neuen Vertrages zwischen Wirtschaftswissenschaft und Gesellschaft an. Sie diskutieren die Chancen, Möglichkeiten und die Verantwortung transformativer Wirtschaftswissenschaft (in besonderem Hinblick auf Nachhaltigkeit) und betten diese in den wissenschaftlichen Diskurs ein. Transparenz, Reflexivität, Werbebezug, Partizipation und Umgestaltung von Forschung und Lehre - das sind nach Ansicht der Autor(inn)en die fünf Bedingungen, welche eine transformative Wirtschaftswissenschaft genügen muss. Der Artikel dient als Denk- und Diskussionsanstoß innerhalb der Wirtschaftswissenschaften sowie auch zwischen Wirtschaftswissenschaft und jenen außenwissenschaftlichen Akteuren, die in gesellschaftlicher und ökonomischer Transformation in Richtung Nachhaltigkeit engagiert sind. Die Spiekerrooger Klimagespräche 2016 werden darauf aufbauen

Cryopreserving Jewish Motherhood: Egg Freezing in Israel and the United States

Oocyte cryopreservation (i.e., egg freezing) is one of the newest forms of assisted reproduction and is increasingly being used primarily by two groups of women: (1) young cancer patients at risk of losing their fertility through cytotoxic chemotherapy (i.e., medical egg freezing); and (2) single professionals in their late 30s who are facing age- related fertility decline in the absence of reproductive partners (i.e., elective egg freezing). Based on a binational ethnographic study, this article examines the significance of egg freezing among Jewish women in Israel and the United States. As they face the Jewish maternal imperative, these women are turning to egg freezing to relieve both medical and marital uncertainties. In both secular and religious Jewish contexts, egg freezing is now becoming naturalized as acceptable and desirable precisely because it cryopreserves Jewish motherhood, keeping reproductive options open for Jewish women, and serving as a protective self- preservation technology within their pronatalist social environments.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170266/1/maq12643.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170266/2/maq12643_am.pd